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Hsueh K, Lee H, Ho K, Chang L, Yang S, Chien M. Disease-Associated Risk Variants and Expression Levels of the lncRNA, CDKN2B-AS1, Are Associated With the Progression of HCC. J Cell Mol Med 2025; 29:e70496. [PMID: 40105653 PMCID: PMC11921468 DOI: 10.1111/jcmm.70496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 03/03/2025] [Accepted: 03/06/2025] [Indexed: 03/20/2025] Open
Abstract
The most susceptible loci of hepatocellular carcinoma (HCC) identified by genome-wide association studies are located in non-coding regions. The antisense non-coding RNA at the INK4 locus (ANRIL), also known as cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1), is a long non-coding (lnc)RNA situated within and antisense to genes encoding CDKN2A/B on chromosome 9p21.3. Single-nucleotide polymorphisms (SNPs) within CDKN2B-AS1 are associated with several cancer types, but their impacts on HCC remain unclear. In this study, we investigated the effects of CDKN2B-AS1 SNPs on both the susceptibility to HCC and its clinicopathological development. Five CDKN2B-AS1 SNP loci-rs564398 (T/C), rs1333048 (A/C), rs1537373 (G/T), rs2151280 (A/G) and rs8181047 (G/A)-were analysed using a TaqMan allelic discrimination assay for genotyping in a cohort of 810 HCC patients and 1190 healthy controls. Under the dominant model, HCC patients with at least one minor C-allele of rs564398 showed a lower risk of liver cirrhosis (odds ratio (OR) = 0.677). Additionally, HCC patients with the GT + TT genotype of rs1537373 had a reduced risk of developing large tumours (T3 + T4) and advanced clinical stages (III/IV), particularly in the male population (OR = 0.644 and 0.679). Furthermore, data from The Cancer Genome Atlas revealed that CDKN2B-AS1 expression levels were elevated in HCC tissues compared to normal tissues and were correlated with advanced T stages, high histological grades and poor prognoses. Our findings suggest that CDKN2B-AS1 levels and its polymorphic variants at rs564398 and rs1537373 may influence the clinicopathological development and progression of HCC in a Taiwanese population.
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Affiliation(s)
- Kuan‐Chun Hsueh
- Division of General Surgery, Department of SurgeryTungs' Taichung Metroharbor HospitalTaichungTaiwan
- Department of Post‐Baccalaureate MedicineCollege of Medicine, National Chung Hsing UniversityTaichungTaiwan
| | - Hsiang‐Lin Lee
- School of MedicineChung Shan Medical UniversityTaichungTaiwan
- Department of SurgeryChung Shan Medical University HospitalTaichungTaiwan
| | - Kuo‐Hao Ho
- Graduate Institute of Clinical Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
| | - Lun‐Ching Chang
- Department of Mathematics and StatisticsFlorida Atlantic UniversityBoca RatonFloridaUSA
| | - Shun‐Fa Yang
- Institute of Medicine, Chung Shan Medical UniversityTaichungTaiwan
- Department of Medical ResearchChung Shan Medical University HospitalTaichungTaiwan
| | - Ming‐Hsien Chien
- Graduate Institute of Clinical Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
- Pulmonary Research Center, Wan Fang HospitalTaipei Medical UniversityTaipeiTaiwan
- Traditional Herbal Medicine Research CenterTaipei Medical University HospitalTaipeiTaiwan
- TMU Research Center of Cancer Translational MedicineTaipei Medical UniversityTaipeiTaiwan
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Chen R, Zhao M, An Y, Liu D, Tang Q. GBAP1 functions as a tumor promotor in hepatocellular carcinoma via the PI3K/AKT pathway. BMC Cancer 2023; 23:628. [PMID: 37407932 DOI: 10.1186/s12885-023-11107-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 06/23/2023] [Indexed: 07/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is common worldwide, and novel therapeutic targets and biomarkers are needed to improve outcomes. In this study, bioinformatics analyses combined with in vitro and in vivo assays were used to identify the potential therapeutic targets. Differentially expressed genes (DEG) in HCC were identified by the intersection between The Cancer Genome Atlas and International Cancer Genome Consortium data. The DEGs were evaluated by a gene set enrichment analysis as well as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. A protein interaction network, univariate Cox regression, and Lasso regression were used to screen out hub genes correlated with survival. Increased expression of the long noncoding RNA GBAP1 in HCC was confirmed in additional datasets and its biological function was evaluated in HCC cell lines and nude mice. Among 121 DEGs, GBAP1 and PRC1 were identified as hub genes with significant prognostic value. Overexpression of GBAP1 in HCC was confirmed in 21 paired clinical tissues and liver cancer or normal cell lines. The inhibition of GBAP1 expression reduced HCC cell proliferation and promoted apoptosis by inactivating the PI3K/AKT pathway in vitro and in vivo. Therefore, GBAP1 has a pro-oncogenic function in HCC and is a candidate prognostic biomarker and therapeutic target.
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Affiliation(s)
- Rong Chen
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China.
| | - Meng Zhao
- Medical college, Henan University of Traditional Chinese Medicine, 450001, Henan Province, China
| | - Yanli An
- Jiangsu Provincial Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Dongfang Liu
- Jiangsu Provincial Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China
| | - Qiusha Tang
- Medical School of Southeast University, Nanjing, 210009, Jiangsu Province, China
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Fu L, Wang X, Yang Y, Chen M, Kuerban A, Liu H, Dong Y, Cai Q, Ma M, Wu X. Septin11 promotes hepatocellular carcinoma cell motility by activating RhoA to regulate cytoskeleton and cell adhesion. Cell Death Dis 2023; 14:280. [PMID: 37080972 PMCID: PMC10119145 DOI: 10.1038/s41419-023-05726-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 02/25/2023] [Accepted: 03/09/2023] [Indexed: 04/22/2023]
Abstract
Septins as GTPases in the cytoskeleton, are linked to a broad spectrum of cellular functions, including cell migration and the progression of hepatocellular carcinoma (HCC). However, roles of SEPT11, the new member of septin, have been hardly understood in HCC. In the study, the clinical significance and biological function of SEPT11 in HCC was explored. SEPT11 was screened out by combining ATAC-seq with mRNA-seq. Role of SEPT11 in HCC was further investigated by using overexpression, shRNA and CRISPR/Cas9-mediated SEPT11-knockout cells or in vivo models. We found RNA-seq and ATAC-seq highlights LncRNA AY927503 (AY) induced SEPT11 transcription, resulting in Rho GTPase activation and cytoskeleton actin aggregation. The GTP-binding protein SEPT11 is thus considered, as a downstream factor of AY, highly expressed in various tumors, including HCC, and associated with poor prognosis of the patients. In vitro, SEPT11 overexpression promotes the migration and invasion of HCC cells, while SEPT11-knockout inhibits migration and invasion. In vivo, SEPT11-overexpressed HCC cells show high metastasis incidents but don't significantly affect proliferation. Meanwhile, we found SEPT11 targets RhoA, thereby regulating cytoskeleton rearrangement and abnormal cell adhesion through ROCK1/cofilin and FAK/paxillin signaling pathways, promoting invasion and migration of HCC. Further, we found SEPT11 facilitates the binding of GEF-H1 to RhoA, which enhances the activity of RhoA. Overall, our study confirmed function of SEPT11 in promoting metastasis in HCC, and preliminarily explored its related molecular mechanism. SEPT11 acts as an oncogene in HCC, also draws further interest regarding its clinical application as a potential therapeutic target.
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Affiliation(s)
- Lisheng Fu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Department of Cardiology of Huadong Hospital Affiliated to Fudan University, Fudan University, 200032, Shanghai, People's Republic of China
| | - Xiaoyan Wang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, 200032, Shanghai, People's Republic of China
| | - Ying Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Department of Cardiology of Huadong Hospital Affiliated to Fudan University, Fudan University, 200032, Shanghai, People's Republic of China
| | - MeiHua Chen
- NHC Key Laboratory of Glycoconjugates, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, People's Republic of China
| | - Adilijiang Kuerban
- Department of Cardiology, Huadong Hospital Affiliated to Fudan University, Fudan University, 200040, Shanghai, People's Republic of China
| | - Haojie Liu
- NHC Key Laboratory of Glycoconjugates, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, People's Republic of China
| | - Yiwei Dong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Department of Cardiology of Huadong Hospital Affiliated to Fudan University, Fudan University, 200032, Shanghai, People's Republic of China
| | - QianQian Cai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Department of Cardiology of Huadong Hospital Affiliated to Fudan University, Fudan University, 200032, Shanghai, People's Republic of China.
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, 201318, Shanghai, China.
| | - Mingzhe Ma
- Department of Gastric Surgery, Shanghai Cancer Center of Fudan University, 200032, Shanghai, People's Republic of China.
| | - XingZhong Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, and Department of Cardiology of Huadong Hospital Affiliated to Fudan University, Fudan University, 200032, Shanghai, People's Republic of China.
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Li D, Fan X, Li Y, Yang J, Lin H. The paradoxical functions of long noncoding RNAs in hepatocellular carcinoma: Implications in therapeutic opportunities and precision medicine. Genes Dis 2022; 9:358-369. [PMID: 35224152 PMCID: PMC8843871 DOI: 10.1016/j.gendis.2020.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 10/22/2020] [Accepted: 11/24/2020] [Indexed: 11/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most aggressive and lethal diseases with poor prognosis, worldwide. However, the mechanisms underlying HCC have not been comprehensively elucidated. With the recent application of high-throughput sequencing techniques, a diverse catalogue of differentially expressed long non-coding RNAs (lncRNA) in cancer have been shown to participate in HCC. Rather than being "transcriptional noise," they are emerging as important regulators of many biological processes, including chromatin remodelling, transcription, alternative splicing, translational and post-translational modification. Moreover, lncRNAs have dual effects in the development and progression of HCC, including oncogenic and tumour-suppressive roles. Collectively, recently data point to lncRNAs as novel diagnostic and prognostic biomarkers with satisfactory sensitivity and specificity, as well as being therapeutic targets for HCC patients. In this review, we highlight recent progress of the molecular patterns of lncRNAs and discuss their potential clinical application in human HCC.
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Affiliation(s)
- Duguang Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Xiaoxiao Fan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Yirun Li
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Jing Yang
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
| | - Hui Lin
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
- Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China
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Fang D, Wang MR, Guan JL, Han YY, Sheng JQ, Tian DA, Li PY. Bromodomain-containing protein 9 promotes hepatocellular carcinoma progression via activating the Wnt/β-catenin signaling pathway. Exp Cell Res 2021; 406:112727. [PMID: 34370992 DOI: 10.1016/j.yexcr.2021.112727] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 06/08/2021] [Accepted: 07/02/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Epigenetic dysregulation participates in the initiation and progression of hepatocellular carcinoma (HCC). Bromodomain-containing protein 9 (BRD9) can identify acetylated lysine residues, contributing to several cancers. The function and molecular mechanism of BRD9 in HCC remain poorly understood. METHODS BRD9 levels in tissues and cells of HCC and normal liver were evaluated using bioinformatic analysis, real-time PCR, and western blot. BRD9's association with clinical outcomes was investigated via survival analyses. Biological behaviors and pathways related to BRD9 were predicted using gene set enrichment analysis. BRD9's role in proliferation was verified via cell counting kit 8, colony formation, and 5-Ethynyl-2'-deoxyuridine assays. Its role in the cell cycle and apoptosis was assessed using flow cytometry. The role of BRD9 in vivo was investigated using xenograft tumor models. A rescue assay was performed to investigate the molecular mechanism of BRD9. RESULTS BRD9 was markedly upregulated in HCC and higher BRD9 expression was associated with higher grade, advanced stage, greater tumor size, and poorer prognosis. BRD9 overexpression enhanced cell proliferation, cell cycle progress, but impeded cell apoptosis. BRD9 downregulation had the opposite effects. In vivo, BRD9 promoted xenograft tumor growth. Mechanistically, BRD9 activated Wnt/β-catenin signaling, obstruction of which abrogated BRD9-mediated tumorigenesis. CONCLUSION Increased BRD9 in HCC correlated with poor prognosis, which functioned via activating Wnt/β-catenin signaling. Thus, BRD9 might be a promising biomarker and therapeutic target for patients with HCC.
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Affiliation(s)
- Dan Fang
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Mu-Ru Wang
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jia-Lun Guan
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Ying-Ying Han
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jia-Qi Sheng
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Clinical Medical Research Center of Hepatic Surgery in Hubei Province, Wuhan, China.
| | - De-An Tian
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Pei-Yuan Li
- Division of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Gastroenterology, Wenchang People's Hospital, Hainan, China.
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Hu S, Liu J, Feng S, Wang Y, Liu H. LncRNA SUMO1P3 acts as a prognostic biomarker and promotes hepatocellular carcinoma growth and metastasis. Aging (Albany NY) 2021; 13:12479-12492. [PMID: 33902004 PMCID: PMC8148505 DOI: 10.18632/aging.202921] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 01/04/2021] [Indexed: 04/10/2023]
Abstract
Long noncoding RNAs (lncRNAs) are involved in the progression of various cancers, including hepatocellular carcinoma (HCC). However, the biological functions of lncRNA small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3) and the underlying mechanisms remain unclear. In this study, we revealed that SUMO1P3 expression was enhanced in HCC tissues and cell lines, positively associating with tumor size and number, poor differentiation, lymphatic and distant metastasis, TNM stage, and poor prognosis in HCC patients. In vitro assays showed that SUMO1P3 depletion reduced HCC cell viability and proliferation by hindering cyclin D1 expression and Akt phosphorylation. SUMO1P3 knockdown induced HCC cell apoptosis, as indicated by increased Bax and cleaved caspase-3 expression and the decreased Bcl-2 level. SUMO1P3 silencing suppressed HCC cell migration and invasion by increasing epithelial marker E-cadherin expression and decreasing mesenchymal marker vimentin expression, as well as reducing matrix metalloproteinase (MMP)-2 and MMP-9 levels. Consistently, SUMO1P3 depletion in HCC cells retarded tumor growth and lung metastasis in vivo. Overall, these results supported the applicability of SUMO1P3 as a useful predictor of HCC prognosis and a potential therapeutic target for HCC patients.
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Affiliation(s)
- Shu Hu
- Medical College, Henan University of Science and Technology, Luoyang 471003, Henan, China
| | - Jiancheng Liu
- Medical College, Henan University of Science and Technology, Luoyang 471003, Henan, China
| | - Shuying Feng
- Medical College, Henan University of Science and Technology, Luoyang 471003, Henan, China
| | - Yue Wang
- Medical College, Henan University of Science and Technology, Luoyang 471003, Henan, China
| | - Hongchao Liu
- Medical College, Henan University of Science and Technology, Luoyang 471003, Henan, China
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Revealing the clinical significance and prognostic value of small nucleolar RNA SNORD31 in hepatocellular carcinoma. Biosci Rep 2021; 40:225778. [PMID: 32697317 PMCID: PMC7376641 DOI: 10.1042/bsr20201479] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 06/26/2020] [Accepted: 07/06/2020] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND For lack of accurate early diagnosis and prognostic assessment, hepatocellular carcinoma (HCC) becomes severe challenge with the fourth cancer-related mortality. Recently, non-coding RNA (ncRNA) was identified to make functions in progression of various tumors. Among that, a novel ncRNA, small nucleolar RNA C/D box 31 (SNORD31) was suggested in previous study to function as potential tumor suppressing role. In the present study, we aimed to investigate the expression patterns and clinical significance of SNORD31 in HCC. METHODS SNORD31 expression was calculated in HCC cell lines as well as clinical specimens by RT-PCR. HCC patients were subdivided into high and low SNORD31 expression groups and their clinical characteristics were compared. Besides, the association between SNORD31 expression and postoperative prognosis was evaluated using Kaplan-Meier and Cox regression analysis. RESULTS Compared with corresponding normal reference, expression levels of SNORD31 were significantly down-regulated in both HCC cell lines and clinical specimens (P<0.01). Moreover, low SNORD31 expression was remarkably correlated with large tumor diameter, high incidence of vessel carcinoma embolus and capsular invasion, severe tumor differentiation and tumor-node-metastasis (TNM) stage (P<0.05). In the following analysis, HCC patients with low SNORD31 expression were independently inclined with poor tumor-free (median time: 9.17 vs 48.8 months, low vs high, P<0.001) as well as long-term survival (LTS; median time: 40.26 vs 55.41 months, low vs high, P=0.002). CONCLUSIONS The ncRNA SNORD31 was proved to be commonly down-regulated in HCC and was independently associated with multiple malignant characteristics and long-term prognosis of HCC patients, which implied that SNORD31 possessed potential as a novel HCC biomarker.
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Zhang J. Targeting mTOR by CZ415 Suppresses Cell Proliferation and Promotes Apoptosis via Lipin-1 in Cervical Cancer In Vitro and In Vivo. Reprod Sci 2021; 28:524-531. [PMID: 32944878 DOI: 10.1007/s43032-020-00313-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/03/2020] [Indexed: 12/18/2022]
Abstract
CZ415, a novel inhibitor of mammalian target of rapamycin (mTOR) kinase, has demonstrated anti-tumor activity in several types of cancer. However, its biological function and underlying mechanism of action in cervical cancer (CC) have not been fully studied. Two CC cell lines (Hela and Siha) were treated with increasing concentrations of CZ415. Cell viability was tested with the CCK-8 assay, cell proliferation was determined by Edu staining and the colony formation assay, and apoptosis was determined by flow cytometry and Hoechst 33342 staining. Protein expression was evaluated by western blotting. A nude mouse xenograft model was used to confirm the anti-tumor activity of CZ415 in vivo. Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining were performed on samples of tumor tissue. Results showed that CZ415 inhibited CC cell survival in a dose- and time-dependent manner, and 100 nanomolar and 48 h were the optimal conditions. In vitro and in vivo experiments showed that treatment with CZ415 significantly inhibited spheroid formation, cell proliferation, and tumor growth. Further studies showed that the anti-cancer effects of CZ415 were due to an induction of apoptosis, which was accompanied by an upregulation of Bax and downregulation of Bcl-2 through Lipin-1. CZ415 also reduced the levels of mTOR/STAT3 expression. However, these phenotypic changes were reversed by overexpression of Lipin-1. Our results suggest that the novel mTOR inhibitor CZ415 mediates tumor malignancy via Lipin-1 and might be useful for treating CC.
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Affiliation(s)
- Jinfeng Zhang
- Department of Women's Health Care, Xiaonan District Maternity and Child Healthcare Hospital, Xiaogan City, 432000, Hubei Province, China.
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Luo YD, Fang L, Yu HQ, Zhang J, Lin XT, Liu XY, Wu D, Li GX, Huang D, Zhang YJ, Chen S, Jiang Y, Shuai L, He Y, Zhang LD, Bie P, Xie CM. p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma. J Hepatol 2021; 74:96-108. [PMID: 32738450 DOI: 10.1016/j.jhep.2020.07.036] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 06/25/2020] [Accepted: 07/21/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS p53 mutations occur frequently in human HCC. Activation of the mammalian target of rapamycin (mTOR) pathway is also associated with HCC. However, it is still unknown whether these changes together initiate HCC and can be targeted as a potential therapeutic strategy. METHODS We generated mouse models in which mTOR was hyperactivated by loss of tuberous sclerosis complex 1 (Tsc1) with or without p53 haplodeficiency. Primary cells were isolated from mouse livers. Oncogenic signalling was assessed in vitro and in vivo, with or without targeted inhibition of a single molecule or multiple molecules. Transcriptional profiling was used to identify biomarkers predictive of HCC. Human HCC materials were used to corroborate the findings from mouse models. RESULTS p53 haploinsufficiency facilitates mTOR signalling via the PTEN/PI3K/Akt axis, promoting HCC tumorigenesis and lung metastasis. Inhibition of PI3K/Akt reduced mTOR activity, which effectively enhanced the anticancer effort of an mTOR inhibitor. ATP-binding cassette subfamily C member 4 (Abcc4) was found to be responsible for p53 haploinsufficiency- and Tsc1 loss-driven HCC tumorigenesis. Moreover, in clinical HCC samples, Abcc4 was specifically identified an aggressive subtype. The mTOR inhibitor rapamycin significantly reduced hepatocarcinogenesis triggered by Tsc1 loss and p53 haploinsufficiency in vivo, as well as the biomarker Abcc4. CONCLUSIONS Our data advance the current understanding of the activation of the PTEN/PI3K/Akt/mTOR axis and its downstream target Abcc4 in hepatocarcinogenesis driven by p53 reduction and Tsc1 loss. Targeting mTOR, an unexpected vulnerability in p53 (haplo)deficiency HCC, can be exploited therapeutically to treat Abcc4-positive patients with HCC. LAY SUMMARY Tsc1 loss facilitates the p53 (haplo)insufficiency-mediated activation of the PTEN/Akt/mTOR axis, leading to the elevated expression of Abcc4 to drive HCC tumorigenesis and metastasis in mice. Inhibition of mTOR protects against p53 haploinsufficiency and Tsc1 loss-triggered tumour-promoting activity, providing a new approach for treating an aggressive subtype of HCC exhibiting high Abcc4 expression.
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Affiliation(s)
- Yuan-Deng Luo
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Lei Fang
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Hong-Qiang Yu
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jie Zhang
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiao-Tong Lin
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiao-Yu Liu
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Di Wu
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Gui-Xi Li
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Deng Huang
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yu-Jun Zhang
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Shu Chen
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yan Jiang
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Ling Shuai
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yu He
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Lei-Da Zhang
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
| | - Ping Bie
- Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Chongqing Medical University (General Hospital), Chongqing, China.
| | - Chuan-Ming Xie
- Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
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Xia Q, Shu Z, Ye T, Zhang M. Identification and Analysis of the Blood lncRNA Signature for Liver Cirrhosis and Hepatocellular Carcinoma. Front Genet 2020; 11:595699. [PMID: 33365048 PMCID: PMC7750531 DOI: 10.3389/fgene.2020.595699] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022] Open
Abstract
As one of the most common malignant tumors, hepatocellular carcinoma (HCC) is the fifth major cause of cancer-associated mortality worldwide. In 90% of cases, HCC develops in the context of liver cirrhosis and chronic hepatitis B virus (HBV) infection is an important etiology for cirrhosis and HCC, accounting for 53% of all HCC cases. To understand the underlying mechanisms of the dynamic chain reactions from normal to HBV infection, from HBV infection to liver cirrhosis, from liver cirrhosis to HCC, we analyzed the blood lncRNA expression profiles from 38 healthy control samples, 45 chronic hepatitis B patients, 46 liver cirrhosis patients, and 46 HCC patients. Advanced machine-learning methods including Monte Carlo feature selection, incremental feature selection (IFS), and support vector machine (SVM) were applied to discover the signature associated with HCC progression and construct the prediction model. One hundred seventy-one key HCC progression-associated lncRNAs were identified and their overall accuracy was 0.823 as evaluated with leave-one-out cross validation (LOOCV). The accuracies of the lncRNA signature for healthy control, chronic hepatitis B, liver cirrhosis, and HCC were 0.895, 0.711, 0.870, and 0.826, respectively. The 171-lncRNA signature is not only useful for early detection and intervention of HCC, but also helpful for understanding the multistage tumorigenic processes of HCC.
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Affiliation(s)
- Qi Xia
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory for Biomedical Engineering of Ministry of Education, Zhejiang University, Hangzhou, China.,Zhejiang University, Hangzhou, China
| | - Zheyue Shu
- Zhejiang University, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
| | - Ting Ye
- Zhejiang University, Hangzhou, China
| | - Min Zhang
- Zhejiang University, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.,Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
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11
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Li L, Song X, Lv Y, Jiang Q, Fan C, Huang D. Landscape of associations between long non-coding RNAs and infiltrating immune cells in liver hepatocellular carcinoma. J Cell Mol Med 2020; 24:11243-11253. [PMID: 32910548 PMCID: PMC7576285 DOI: 10.1111/jcmm.15690] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/27/2020] [Accepted: 07/12/2020] [Indexed: 12/25/2022] Open
Abstract
Liver hepatocellular carcinoma (LIHC) can be detected by the immune system; however, it acquires features for evasion of immune surveillance during its origin and development. Long non‐coding RNAs (lncRNAs) are critical as immune regulators in cancers; nevertheless, the biological functions and mechanisms of lncRNAs in evasion of immune system by LIHC remain unclear. In this study, an integrated and computational approach was developed to identify immune‐related lncRNAs and to divide LIHC patients into diverse immune‐related risk groups based on the expression profiles of coding genes and lncRNAs. LIHC‐specific genes and lncRNAs in 17 immune cell populations were identified and analysed. Gene and lncRNA co‐expressing networks for diverse immune cell populations were constructed and analysed. Some imported immune‐related lncRNAs, such as MIR9‐3HG, were also identified. The LIHC patients comprised three different groups based on immune‐related risk. LIHC patients possessing a greater diversity of immune cell populations had better survival prognosis. The collective data are evidence of a credible computational model that can prioritize novel immune‐related lncRNAs and depict the atlas of immune‐related lncRNAs in LIHC. These findings will further the understanding of lncRNA function and advance the identification of immunotherapy targets in LIHC.
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Affiliation(s)
- Li Li
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaowei Song
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yanju Lv
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qiuying Jiang
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chengjuan Fan
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dayong Huang
- Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
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12
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Wu Y, Zhang Y, Qin X, Geng H, Zuo D, Zhao Q. PI3K/AKT/mTOR pathway-related long non-coding RNAs: roles and mechanisms in hepatocellular carcinoma. Pharmacol Res 2020; 160:105195. [PMID: 32916254 DOI: 10.1016/j.phrs.2020.105195] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/30/2020] [Accepted: 09/03/2020] [Indexed: 01/27/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide with high prevalence and lethality. The oncogenic phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is a classic dysregulated pathway involved in the pathogenesis of HCC. However, the underlying mechanism for how PI3K/AKT/mTOR pathway aberrantly activates HCC has not been entirely elucidated. The recognition of the functional roles of long non-coding RNAs (lncRNAs) in PI3K/AKT/mTOR signaling axis sheds light on a new dimension to our understanding of hepatocarcinogenesis. In this review, we comprehensively summarize 67 dysregulated PI3K/AKT/mTOR pathway-related lncRNAs in HCC. Many studies have indicated that the 67 dysregulated lncRNAs show oncogenic or anti-oncogenic effects in HCC by regulation on epigenetic, transcriptional and post-transcriptional levels and they play pivotal roles in the initiation of HCC in diverse biological processes like proliferation, metastasis, drug resistance, radio-resistance, energy metabolism, autophagy and so on. Besides, many of these lncRNAs are associated with clinicopathological features and clinical prognosis in HCC, which may provide a potential future application in the diagnosis and therapy of HCC.
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Affiliation(s)
- Yuting Wu
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Yingshi Zhang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Xiaochun Qin
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Haobin Geng
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
| | - Qingchun Zhao
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; Department of Pharmacy, General Hospital of Northern Theater Command, 83 Wenhua Road, Shenhe District, Shenyang 110840, China.
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13
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Li C, Yang J, Liu C, Wang X, Zhang L. Long non-coding RNAs in hepatocellular carcinoma: Ordering of the complicated lncRNA regulatory network and novel strategies for HCC clinical diagnosis and treatment. Pharmacol Res 2020; 158:104848. [DOI: 10.1016/j.phrs.2020.104848] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 02/07/2023]
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14
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Shao C, Liu G, Zhang X, Li A, Guo X. Long Noncoding RNA RMRP Suppresses the Tumorigenesis of Hepatocellular Carcinoma Through Targeting microRNA-766. Onco Targets Ther 2020; 13:3013-3024. [PMID: 32308432 PMCID: PMC7152554 DOI: 10.2147/ott.s243736] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2019] [Accepted: 03/17/2020] [Indexed: 12/13/2022] Open
Abstract
PURPOSE This study aimed to explore the regulatory effect of long noncoding RNA (lncRNA) ribonuclease mitochondrial RNA processing gene (RMRP) on hepatocellular carcinoma (HCC). METHODS The expression of RMRP in HCC tissues and cell lines was assessed by qRT-PCR. Kaplan-Meier method was utilized to analyze the correlation between RMRP expression and the survival of HCC patients. MHCC97H and HuH7 cells were transfected with pcDNA3.1-RMRP or pcDNA3.1, respectively. MTT and flow cytometry assays were conducted to examine the proliferation and apoptosis of HCC cells, respectively. The migration and invasion of HCC cells were assessed using wound healing and transwell assays, respectively. StarBase3.0 and dual-luciferase reporter gene assay were used to identify the target relationship between miR-766 and RMRP. A xenografted tumor model was established in rats to evaluate the effect of RMRP in vivo. RESULTS RMRP was down-regulated in HCC tissues and cells. Low expression of RMRP was correlated with poor survival of HCC patients. The A495 value and colony number were significantly decreased in pcDNA3.1-RMRP-transfected MHCC97H and HuH7 cells. The apoptosis rate was significantly increased in pcDNA3.1-RMRP-transfected MHCC97H and HuH7 cells. The migration rate and the number of invasive cells were significantly decreased in pcDNA3.1-RMRP-transfected MHCC97H and HuH7 cells. MiR-766 was a target of RMRP and eliminated the anti-tumor effect of RMRP on MHCC97H cells. The up-regulation of RMRP suppressed the growth of xenograft tumors in rats. CONCLUSION Overexpression of RMRP suppressed the tumorigenesis of HCC by targeting miR-766.
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Affiliation(s)
- Cunhua Shao
- Department of Hepatobiliary Surgery, Dongying People’s Hospital, Dongying City257091, People’s Republic of China
| | - Gongpan Liu
- Department of Hepatobiliary Surgery, Dongying People’s Hospital, Dongying City257091, People’s Republic of China
| | - Xiaobin Zhang
- Department of Hepatobiliary Surgery, Dongying People’s Hospital, Dongying City257091, People’s Republic of China
| | - Anyun Li
- Department of General Surgery, Dongying Hong Gang Hospital, Dongying City257000, People’s Republic of China
| | - Xingjun Guo
- Department of Hepatobiliary Surgery, Dongying People’s Hospital, Dongying City257091, People’s Republic of China
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15
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Zheng H, Qin Z, Qiu X, Zhan M, Wen F, Xu T. Cost-effectiveness analysis of ramucirumab treatment for patients with hepatocellular carcinoma who progressed on sorafenib with α-fetoprotein concentrations of at least 400 ng/ml. J Med Econ 2020; 23:347-352. [PMID: 31856618 DOI: 10.1080/13696998.2019.1707211] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 12/06/2019] [Accepted: 12/16/2019] [Indexed: 02/08/2023]
Abstract
Objective: This study aimed to compare the cost-effectiveness of ramucirumab versus placebo for patients with hepatocellular carcinoma who progressed on sorafenib with α-fetoprotein concentrations (AFP) of at least 400 ng/ml in the United States.Methods: A Markov model was constructed to assess the cost-effectiveness of ramucirumab. Health outcomes were measured as quality-adjusted life years (QALYs). With TreeAge software, the disease process was modeled as three health states: progression-free survival (PFS), progressive disease (PD), and death. Costs were extracted from the REACH-2 trial, and utility was derived from published literature. Incremental cost-effectiveness ratios (ICERs) were calculated to compare ramucirumab with placebo. Probabilistic sensitivity analyses were developed to examine the robustness of the results.Results: In the base case analysis, ramucirumab therapy had a cost of $55,508.41 and generated 0.54 QALYs, while placebo therapy had a cost of $761.09 and generated 0.47 QALYs, leading to an additional $54,747.32 in costs and 0.07 QALYs. The ICER was $782,104.57 per QALY, which was much higher than the willingness-to-pay threshold of $100,000 per QALY. According to sensitivity analyses, the utility of PD in the two groups was the dominant parameter influencing the ICER.Conclusion: Although ramucirumab was associated with prolonged survival for patients with advanced hepatocellular carcinoma who progressed on sorafenib treatment with an AFP of at least 400 ng/ml, it is not a cost-effective treatment from a United States payer perspective.
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Affiliation(s)
- Hanrui Zheng
- Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhou Qin
- Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | | | - Mei Zhan
- Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Feng Wen
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- West China Biomedical Big Data Center, Sichuan University, Chengdu, China
| | - Ting Xu
- Department of Clinical Pharmacy, West China Hospital, Sichuan University, Chengdu, China
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16
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Chen CY, Chen CC, Chuang WY, Leu YL, Ueng SH, Hsueh C, Yeh CT, Wang TH. Hydroxygenkwanin Inhibits Class I HDAC Expression and Synergistically Enhances the Antitumor Activity of Sorafenib in Liver Cancer Cells. Front Oncol 2020; 10:216. [PMID: 32158695 PMCID: PMC7052045 DOI: 10.3389/fonc.2020.00216] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 02/07/2020] [Indexed: 12/13/2022] Open
Abstract
Abnormal histone deacetylase (HDAC) expression is closely related to cancer development and progression. Many HDAC inhibitors have been widely used in cancer treatment; however, severe side effects often limit their clinical application. In this study, we attempted to identify natural compounds with HDAC inhibitory activity and low physiological toxicity and explored their feasibility and mechanisms of action in liver cancer treatment. A yeast screening system was used to identify natural compounds with HDAC inhibitory activity. Further, western blotting was used to verify inhibitory effects on HDAC in human liver cancer cell lines. Cell functional analysis was used to explore the effects and mechanisms and the in vitro results were verified in BALB/c nude mice. We found that hydroxygenkwanin (HGK), an extract from Daphne genkwa, inhibited class I HDAC expression, and thereby induced expression of tumor suppressor p21 and promoted acetylation and activation of p53 and p65. This resulted in the inhibition of growth, migration, and invasion of liver cancer cells and promoted cell apoptosis. Animal models revealed that HGK inhibited tumor growth in a synergistic manner with sorafenib. HGK inhibited class I HDAC expression and had low physiological toxicity. It has great potential as an adjuvant for liver cancer treatment and may be used in combination with anticancer drugs like sorafenib to improve therapeutic efficacy.
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Affiliation(s)
- Chi-Yuan Chen
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
| | - Chin-Chuan Chen
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Yu Chuang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Taoyuan, Taiwan
| | - Yann-Lii Leu
- Graduate Institute of Natural Products, Chang Gung University, Taoyuan, Taiwan.,Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan.,Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Shir-Hwa Ueng
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Taoyuan, Taiwan
| | - Chuen Hsueh
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Tong-Hong Wang
- Tissue Bank, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.,Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
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17
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Yuan LT, Chang JH, Lee HL, Yang YC, Su SC, Lin CL, Yang SF, Chien MH. Genetic Variants of lncRNA MALAT1 Exert Diverse Impacts on the Risk and Clinicopathologic Characteristics of Patients with Hepatocellular Carcinoma. J Clin Med 2019; 8:jcm8091406. [PMID: 31500187 PMCID: PMC6780489 DOI: 10.3390/jcm8091406] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/26/2019] [Accepted: 09/03/2019] [Indexed: 02/07/2023] Open
Abstract
The long noncoding (lnc)RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), plays a crucial role in the development of hepatocellular carcinoma (HCC). However, potential genetic variants (single nucleotide polymorphisms, SNPs) in MALAT1 that affect the susceptibility and progression of HCC have rarely been explored. Three tagging SNPs, viz., rs3200401 C > T, rs619586 A > G, and rs1194338 C > A, in MALAT1 were genotyped by a TaqMan allelic discrimination assay in 394 HCC patients and 1199 healthy controls. A stratified analysis showed that younger patients (<55 years) with the MALAT1 rs619586 G allele had a decreased risk of HCC under a codominant model (AOR = 0.289, 95% CI: 0.108–0.773, p = 0.013) and dominant model (AOR = 0.286, 95% CI: 0.107–0.765, p = 0.013). Female patients and patients with a smoking habit who carried the CA + AA genotype of rs1194338 had a lower risk of developing vascular invasion (p = 0.049) and a high Child–Pugh grade (B or C) (p = 0.036), respectively. Under the dominant model, smokers with the MALAT1 rs3200401 CT + TT genotype had a higher frequency of hepatitis B virus (HBV) infection (p = 0.034). Moreover, the aspartate aminotransferase was higher in patients with the rs3200401 CT + TT genotype. Furthermore, analyses of clinical datasets revealed that MALAT1 expression level was gradually unregulated during HCC development from normal liver, cirrhotic liver, dysplastic liver to HCC and correlated with poor survival rates in HCC patients, especially in the hepatitis virus-infected population.
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Affiliation(s)
- Lan-Ting Yuan
- Division of Hepatology and Gastroenterology, Department of Internal Medicine, Yuan's General Hospital, Kaohsiung 80249, Taiwan
| | - Jer-Hwa Chang
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
| | - Hsiang-Lin Lee
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Surgery, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Yi-Chieh Yang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Shih-Chi Su
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Chien-Liang Lin
- Department of Pharmacy, FooYin University Hospital, Pingtung 92847, Taiwan
| | - Shun-Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
| | - Ming-Hsien Chien
- Pulmonary Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan.
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18
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Wang X, Zhou X, Liu J, Liu Z, Zhang L, Gong Y, Huang J, Yu L, Wang Q, Yang C, Liao X, Yu T, Han C, Zhu G, Ye X, Peng T. Genome‑wide investigation of the clinical implications and molecular mechanism of long noncoding RNA LINC00668 and protein‑coding genes in hepatocellular carcinoma. Int J Oncol 2019; 55:860-878. [PMID: 31432149 PMCID: PMC6741837 DOI: 10.3892/ijo.2019.4858] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 07/31/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of tumor‑related mortalities worldwide. Long noncoding RNAs have been reported to be associated with tumor initiation, progression and prognosis. The present study aimed to explore the association between long noncoding RNA LINC00668 and its co‑expression correlated protein‑coding genes (PCGs) in HCC. Data of 370 HCC patients from The Cancer Genome Atlas database were used for analysis. LINC00668 and its top 10 PCGs were selected to determine their diagnostic and prognostic value. Molecular mechanisms were explored to identify metabolic processes that LINC00668 and its PCGs are involved in. Prognosis‑related clinical factors and PCGs were used to construct a nomogram for predicting prognosis in HCC. A Connectivity Map was constructed to identify candidate target drugs for HCC. The top 10 PCGs identified were: Pyrimidineregic receptor P2Y4 (P2RY4), signal peptidase complex subunit 2 (SPCS2), family with sequence similarity 86 member C1 (FAM86C1), tudor domain containing 5 (TDRD5), ferritin light chain (FTL), stratifin (SFN), nucleolar complex associated 2 homolog (NOC2L), peroxiredoxin 1 (PRDX1), cancer/testis antigen 2 CTAG2 and leucine zipper and CTNNBIP1 domain containing (LZIC). FAM86C1, CTAG2 and SFN had significant diagnostic value for HCC (total area under the curve ≥0.7, P≤0.05); LINC00668, FAM86C1, TDRD5, FTL and SFN were of significant prognostic value for HCC (all P≤0.05). Investigation into the molecular mechanism indicated that LINC00668 affects cell division, cell cycle, mitotic nuclear division, and drug metabolism cytochrome P450 (all P≤0.05). The Connectivity Map identified seven candidate target drugs for the treatment of HCC, which were: Indolylheptylamine, mimosine, disopyramide, lidocaine, NU‑1025, bumetanide, and DQNLAOWBTJPFKL‑PKZXCIMASA‑N (all P≤0.05). Our findings indicated that LINC00668 may function as an oncogene and its overexpression indicates poor prognosis of HCC. FAM86C1, CTAG2 and SFN are of diagnostic significance, while FAM86C1, TDRD5, FTL and SFN are of prognostic significance for HCC.
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Affiliation(s)
- Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Junqi Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Zhengqian Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Linbo Zhang
- Health Management and Division of Physical Examination, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Yizhen Gong
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Jianlu Huang
- Department of Hepatobiliary Surgery, Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530031, P.R. China
| | - Long Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Qiaoqi Wang
- Department of Medical Cosmetology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530000, P.R. China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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19
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Provvisiero DP, Negri M, de Angelis C, Di Gennaro G, Patalano R, Simeoli C, Papa F, Ferrigno R, Auriemma RS, De Martino MC, Colao A, Pivonello R, Pivonello C. Vitamin D reverts resistance to the mTOR inhibitor everolimus in hepatocellular carcinoma through the activation of a miR-375/oncogenes circuit. Sci Rep 2019; 9:11695. [PMID: 31406139 PMCID: PMC6690984 DOI: 10.1038/s41598-019-48081-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 07/30/2019] [Indexed: 12/15/2022] Open
Abstract
Primary or acquired resistant mechanisms prevent the employment of individualized therapy with target drugs like the mTOR inhibitor everolimus (EVE) in hepatocellular carcinoma (HCC). The current study evaluated the effect of 1,25(OH)2Vitamin D (VitD) treatment on EVE sensitivity in established models of HCC cell lines resistant to everolimus (EveR). DNA content and colony formation assays, which measure the proliferative index, revealed that VitD pre-treatment re-sensitizes EveR cells to EVE treatment. The evaluation of epithelial and mesenchymal markers by western blot and immunofluorescence showed that VitD restored an epithelial phenotype in EveR cells, in which prolonged EVE treatment induced transition to mesenchymal phenotype. Moreover, VitD treatment prompted hepatic miRNAs regulation, evaluated by liver miRNA finder qPCR array. In particular, miR-375 expression was up-regulated by VitD in EveR cells, in which miR-375 was down-regulated compared to parental cells, with consequent inhibition of oncogenes involved in drug resistance and epithelial-mesenchymal transition (EMT) such as MTDH, YAP-1 and c-MYC. In conclusion, the results of the current study demonstrated that VitD can re-sensitize HCC cells resistant to EVE treatment triggering miR-375 up-regulation and consequently down-regulating several oncogenes responsible of EMT and drug resistance.
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Affiliation(s)
- Donatella Paola Provvisiero
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Mariarosaria Negri
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Cristina de Angelis
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.,Dipartimento di Sanità Pubblica, Università Federico II di Napoli, Naples, Italy
| | - Gilda Di Gennaro
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Roberta Patalano
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.,Dipartimento di Sanità Pubblica, Università Federico II di Napoli, Naples, Italy
| | - Chiara Simeoli
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Fortuna Papa
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Rosario Ferrigno
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Renata Simona Auriemma
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Maria Cristina De Martino
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy
| | - Claudia Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy.
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20
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Adebayo Michael AO, Ko S, Tao J, Moghe A, Yang H, Xu M, Russell JO, Pradhan-Sundd T, Liu S, Singh S, Poddar M, Monga JS, Liu P, Oertel M, Ranganathan S, Singhi A, Rebouissou S, Zucman-Rossi J, Ribback S, Calvisi D, Qvartskhava N, Görg B, Häussinger D, Chen X, Monga SP. Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations. Cell Metab 2019; 29:1135-1150.e6. [PMID: 30713111 PMCID: PMC6506359 DOI: 10.1016/j.cmet.2019.01.002] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/03/2018] [Accepted: 01/07/2019] [Indexed: 12/12/2022]
Abstract
Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation. In normal livers of mice and humans, pericentral hepatocytes were simultaneously GS and p-mTOR-S2448 positive, as were β-catenin-mutated liver tumors. Genetic disruption of β-catenin signaling or GS prevented p-mTOR-S2448 expression, while its forced expression in β-catenin-deficient livers led to ectopic p-mTOR-S2448 expression. Further, we found notable therapeutic benefit of mTORC1 inhibition in mutant-β-catenin-driven HCC through suppression of cell proliferation and survival. Thus, mTORC1 inhibitors could be highly relevant in the treatment of liver tumors that are β-catenin mutated and GS positive.
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Affiliation(s)
- Adeola O Adebayo Michael
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sungjin Ko
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Junyan Tao
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Akshata Moghe
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Hong Yang
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Meng Xu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Jacquelyn O Russell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Tirthadipa Pradhan-Sundd
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Silvia Liu
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sucha Singh
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Minakshi Poddar
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jayvir S Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Pin Liu
- Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
| | - Michael Oertel
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sarangarajan Ranganathan
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Pediatric Pathology, Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Aatur Singhi
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sandra Rebouissou
- Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris 75010, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, 75010 Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, 93000 Bobigny, France; Université Paris Diderot, IUH, 75010 Paris, France
| | - Jessica Zucman-Rossi
- Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris 75010, France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, 75010 Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, 93000 Bobigny, France; Université Paris Diderot, IUH, 75010 Paris, France
| | - Silvia Ribback
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Diego Calvisi
- Institute of Pathology, University of Greifswald, Greifswald, Germany
| | - Natalia Qvartskhava
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Boris Görg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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21
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Zheng L, You N, Huang X, Gu H, Wu K, Mi N, Li J. COMMD7 Regulates NF-κB Signaling Pathway in Hepatocellular Carcinoma Stem-like Cells. MOLECULAR THERAPY-ONCOLYTICS 2018; 12:112-123. [PMID: 30719501 PMCID: PMC6350112 DOI: 10.1016/j.omto.2018.12.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 12/07/2018] [Indexed: 12/26/2022]
Abstract
Previous studies showed that the COpper Metabolism gene MURR1 Domain (COMMD) family of proteins was abnormally expressed in hepatocellular carcinoma (HCC). This study aimed to explore the roles of COMMD1 and COMMD7 in regulating nuclear factor κB (NF-κB) signaling in HCC stem cells (HCSCs). In vivo, the expression of COMMD7 and COMMD1 was determined in 35 pairs of HCC cancer tissues and adjacent tissues, and the effect of COMMD7 silencing on xenograft tumor growth was evaluated. In vitro, the effects of COMMD7 silencing and COMMD1 overexpression on HCSC function were assessed. Results found that the expression levels of COMMD7 were higher, whereas COMMD1 levels were lower in HCC tissues and HCSCs. COMMD7 silencing or COMMD1 overexpression inhibited cell proliferation, migration, and invasion through suppression of NF-κB p65. Furthermore, COMMD7 positively regulated NF-κB by upregulating protein inhibitor for activated stat 4 (PIAS4). This study demonstrates that COMMD7 has a dual regulatory role in the NF-κB signaling pathway in Nanog+ HCSCs.
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Affiliation(s)
- Lu Zheng
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Army Medical University, PLA, Chongqing, China
| | - Nan You
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Army Medical University, PLA, Chongqing, China
| | - Xiaobing Huang
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Army Medical University, PLA, Chongqing, China
| | - Huiying Gu
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Army Medical University, PLA, Chongqing, China
| | - Ke Wu
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Army Medical University, PLA, Chongqing, China
| | - Na Mi
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Army Medical University, PLA, Chongqing, China
| | - Jing Li
- Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Army Medical University, PLA, Chongqing, China
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22
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NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression. Oncogene 2018; 37:4887-4900. [PMID: 29780166 DOI: 10.1038/s41388-018-0280-6] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 03/29/2018] [Accepted: 03/30/2018] [Indexed: 01/21/2023]
Abstract
Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism and involved in many diseases, including cancer. CFIm25, a subunit of the cleavage factor I encoded by NUDT21, is required for 3'RNA cleavage and polyadenylation. Although it has been recently reported to be involved in glioblastoma tumor suppression, its roles and the underlying functional mechanism remain unclear in other types of cancer. In this study, we characterized NUDT21 in hepatocellular carcinoma (HCC). Reduced expression of NUDT21 was observed in HCC tissue compared to adjacent non-tumorous compartment. HCC patients with lower NUDT21 expression have shorter overall and disease-free survival times than those with higher NUDT21 expression after surgery. Knockdown of NUDT21 promotes HCC cell proliferation, metastasis, and tumorigenesis, whereas forced expression of NUDT21 exhibits the opposite effects. We then performed global APA site profiling analysis in HCC cells and identified considerable number of genes with shortened 3'UTRs upon the modulation of NUDT21 expression. In particular, we further characterized the NUDT21-regulated genes PSMB2 and CXXC5. We found NUDT21 knockdown increases usage of the proximal polyadenylation site in the PSMB2 and CXXC5 3' UTRs, resulting in marked increase in the expression of PSMB2 and CXXC5. Moreover, knockdown of PSMB2 or CXXC5 suppresses HCC cell proliferation and invasion. Taken together, our study demonstrated that NUDT21 inhibits HCC proliferation, metastasis and tumorigenesis, at least in part, by suppressing PSMB2 and CXXC5, and thereby provided a new insight into understanding the connection of HCC suppression and APA machinery.
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23
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Multimodality Molecular Imaging-Guided Tumor Border Delineation and Photothermal Therapy Analysis Based on Graphene Oxide-Conjugated Gold Nanoparticles Chelated with Gd. CONTRAST MEDIA & MOLECULAR IMAGING 2018; 2018:9321862. [PMID: 29853812 PMCID: PMC5964426 DOI: 10.1155/2018/9321862] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Accepted: 03/28/2018] [Indexed: 12/27/2022]
Abstract
Tumor cell complete extinction is a crucial measure to evaluate antitumor efficacy. The difficulties in defining tumor margins and finding satellite metastases are the reason for tumor recurrence. A synergistic method based on multimodality molecular imaging needs to be developed so as to achieve the complete extinction of the tumor cells. In this study, graphene oxide conjugated with gold nanostars and chelated with Gd through 1,4,7,10-tetraazacyclododecane-N,N′,N,N′-tetraacetic acid (DOTA) (GO-AuNS-DOTA-Gd) were prepared to target HCC-LM3-fLuc cells and used for therapy. For subcutaneous tumor, multimodality molecular imaging including photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) and the related processing techniques were used to monitor the pharmacokinetics process of GO-AuNS-DOTA-Gd in order to determine the optimal time for treatment. For orthotopic tumor, MRI was used to delineate the tumor location and margin in vivo before treatment. Then handheld photoacoustic imaging system was used to determine the tumor location during the surgery and guided the photothermal therapy. The experiment result based on orthotopic tumor demonstrated that this synergistic method could effectively reduce tumor residual and satellite metastases by 85.71% compared with the routine photothermal method without handheld PAI guidance. These results indicate that this multimodality molecular imaging-guided photothermal therapy method is promising with a good prospect in clinical application.
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24
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Veiga SR, Ge X, Mercer CA, Hernández-Álvarez MI, Thomas HE, Hernandez-Losa J, Ramón Y Cajal S, Zorzano A, Thomas G, Kozma SC. Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR. Clin Cancer Res 2018; 24:3767-3780. [PMID: 29691292 DOI: 10.1158/1078-0432.ccr-18-0177] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 04/05/2018] [Accepted: 04/19/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mTOR for the treatment of HCC. However, such inhibitors induce hyperglycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor phenformin could reverse both side effects, impose an energetic stress on cancer cells, and suppress the growth of HCC.Experimental Design: Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated preclinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival.Results: We found phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with phenformin, was highly efficacious in controlling tumor burden. However, more strikingly, pretreatment with phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival.Conclusions: Treatment of HCC cells in vitro with the biguanide phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC. Clin Cancer Res; 24(15); 3767-80. ©2018 AACR.
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Affiliation(s)
- Sónia R Veiga
- Laboratory of Cancer Metabolism, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Xuemei Ge
- Laboratory of Cancer Metabolism, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
| | - Carol A Mercer
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio
| | - María I Hernández-Álvarez
- Complex Metabolic Diseases and Mitochondria Group, Institute for Research in Biomedicine (IRB), Barcelona, Spain
| | - Hala Elnakat Thomas
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio
| | - Javier Hernandez-Losa
- Department of Anatomy/Pathology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Santiago Ramón Y Cajal
- Department of Anatomy/Pathology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Antonio Zorzano
- Complex Metabolic Diseases and Mitochondria Group, Institute for Research in Biomedicine (IRB), Barcelona, Spain.,Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - George Thomas
- Laboratory of Cancer Metabolism, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.,Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio.,Physiological Sciences Department, Faculty of Medicine and Health Science, University of Barcelona, Barcelona, Spain
| | - Sara C Kozma
- Laboratory of Cancer Metabolism, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. .,Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio
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25
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Corylin Suppresses Hepatocellular Carcinoma Progression via the Inhibition of Epithelial-Mesenchymal Transition, Mediated by Long Noncoding RNA GAS5. Int J Mol Sci 2018; 19:ijms19020380. [PMID: 29382035 PMCID: PMC5855602 DOI: 10.3390/ijms19020380] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 01/13/2018] [Accepted: 01/18/2018] [Indexed: 12/16/2022] Open
Abstract
Corylin is a flavonoid extracted from the nuts of Psoralea corylifolia L. (Fabaceae), which is a widely used anti-inflammatory and anticancer herb in China. Recent studies revealed antioxidant, anti-inflammatory, and bone differentiation–promoting effects of corylin. However, there are no studies examining the anticancer activity of corylin. In this study, we used cells and animal models to examine the antitumor effects of corylin on hepatocellular carcinoma (HCC) and then studied its downstream regulatory mechanisms. The results showed that corylin significantly inhibited the proliferation, migration, and invasiveness of HCC cells and suppressed epithelial–mesenchymal transition. We found that the anti-HCC mechanism of corylin’s action lies in the upregulation of tumor suppressor long noncoding RNA growth arrest-specific transcript 5 (GAS5) and the activation of its downstream anticancer pathways. In animal experiments, we also found that corylin can significantly inhibit tumor growth without significant physiological toxicity. The above results suggest that corylin has anti-HCC effects and good potential as a clinical treatment.
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26
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Wang TH, Yu CC, Lin YS, Chen TC, Yeh CT, Liang KH, Shieh TM, Chen CY, Hsueh C. Long noncoding RNA CPS1-IT1 suppresses the metastasis of hepatocellular carcinoma by regulating HIF-1α activity and inhibiting epithelial-mesenchymal transition. Oncotarget 2017; 7:43588-43603. [PMID: 27248828 PMCID: PMC5190046 DOI: 10.18632/oncotarget.9635] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 05/09/2016] [Indexed: 01/04/2023] Open
Abstract
Recently, increasing numbers of long noncoding RNAs (lncRNAs), with both oncogenic and tumor-suppressive potential, have been found to be aberrantly expressed in various human cancers. However, the function of lncRNAs in hepatocellular carcinoma (HCC) progression remains largely unknown. In this study, we performed a comprehensive microarray analysis of lncRNA expression using human HCC specimens. After validation in 119 human HCC tissues, we identified a novel tumor suppressor lncRNA, CPS1 intronic transcript 1 (CPS1-IT1). To elucidate the clinical significance of CPS1-IT1 in HCC, correlations between CPS1-IT1 levels, clinical parameters, and survival outcomes were analyzed. In vitro and in vivo functional assays were also performed to dissect the potential underlying mechanisms. Expression of CPS1-IT1 was significantly decreased in 73% of HCC tissues, and patients with low CPS1-IT1 expression had poor survival outcomes. Furthermore, in vitro functional assays indicated that CPS1-IT1 significantly reduced cell proliferation, migration and invasion capacities through reduced Hsp90 binding to and activation of HIF-1α, thereby suppressing the epithelial-mesenchymal transition (EMT). An in vivo animal model also demonstrated the tumor suppressor role of CPS1- IT1 via decreased tumor growth and metastasis. In conclusion, lncRNA CPS1-IT1 acts as a tumor suppressor in HCC by reducing HIF-1α activation and suppressing EMT. The findings of this study establish a function for CPS1-IT1 in HCC progression and suggest its potential as a new prognostic biomarker and target for HCC therapy.
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Affiliation(s)
- Tong-Hong Wang
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan.,Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
| | - Cheng-Chia Yu
- School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.,Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.,Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
| | - Yong-Shiang Lin
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | - Tse-Ching Chen
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Kung-Hao Liang
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Tzong-Ming Shieh
- Department of Dental Hygiene, College of Health Care, China Medical University, Taichung, Taiwan
| | - Chi-Yuan Chen
- Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan.,Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
| | - Chuen Hsueh
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
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27
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Zheng X, Zhang Y, Liu Y, Fang L, Li L, Sun J, Pan Z, Xin W, Huang P. HIF‐2α activated lncRNA NEAT1 promotes hepatocellular carcinoma cell invasion and metastasis by affecting the epithelial‐mesenchymal transition. J Cell Biochem 2017; 119:3247-3256. [DOI: 10.1002/jcb.26481] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 10/31/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Xiaowei Zheng
- Department of PharmacyZhejiang Cancer HospitalHangzhouZhejiangPeople's Republic of China
| | - Yiwen Zhang
- Department of PharmacyZhejiang Cancer HospitalHangzhouZhejiangPeople's Republic of China
| | - Yujia Liu
- Department of PharmacyZhejiang Cancer HospitalHangzhouZhejiangPeople's Republic of China
| | - Luo Fang
- Department of PharmacyZhejiang Cancer HospitalHangzhouZhejiangPeople's Republic of China
| | - Li Li
- Department of PharmacyThe First People's Hospital of Chun'an CountyZhejiangPeople's Republic of China
| | - Jiao Sun
- Department of PharmacyZhejiang Cancer HospitalHangzhouZhejiangPeople's Republic of China
| | - Zongfu Pan
- Department of PharmacyZhejiang Cancer HospitalHangzhouZhejiangPeople's Republic of China
| | - Wenxiu Xin
- Department of PharmacyZhejiang Cancer HospitalHangzhouZhejiangPeople's Republic of China
| | - Ping Huang
- Department of PharmacyZhejiang Cancer HospitalHangzhouZhejiangPeople's Republic of China
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28
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Huo X, Han S, Wu G, Latchoumanin O, Zhou G, Hebbard L, George J, Qiao L. Dysregulated long noncoding RNAs (lncRNAs) in hepatocellular carcinoma: implications for tumorigenesis, disease progression, and liver cancer stem cells. Mol Cancer 2017; 16:165. [PMID: 29061150 PMCID: PMC5651571 DOI: 10.1186/s12943-017-0734-4] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 10/16/2017] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumours with a poor prognosis worldwide. While early stage tumours can be treated with curative approaches such as liver transplantation or surgical resection, these are only suitable for a minority of patients. Those with advanced stage disease are only suitable for supportive approaches and most are resistant to the conventional chemotherapy or radiotherapy. Liver cancer stem cells (LCSCs) are a small subset of cancer cells with unlimited differentiation ability and tumour forming potential. In order to develop novel therapeutic approaches for HCC, we need to understand how the cancer develops and why treatment resistance occurs. Using high-throughput sequencing techniques, a large number of dysregulated long noncoding RNAs (lncRNAs) have been identified, and some of which are closely linked to key aspects of liver cancer pathology, progression, outcomes and for the maintenance of cancer stem cell-like properties. In addition, some lncRNAs are potential biomarkers for HCC diagnosis and may serve as the therapeutic targets. This review summarizes data recently reported lncRNAs that might be critical for the maintenance of the biological properties of LCSCs.
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Affiliation(s)
- Xiaoqi Huo
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Shuanglin Han
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
- Department of Gastroenterology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, 116027, China
| | - Guang Wu
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Olivier Latchoumanin
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Gang Zhou
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Lionel Hebbard
- Department of Molecular and Cell Biology, Centre for Comparative Genomics, The Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Australian Institute of Tropical Health and Medicine, QLD, Townsville, 4811, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Liang Qiao
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, 2145, Australia.
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Niu L, Liu L, Yang S, Ren J, Lai PBS, Chen GG. New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies. Biochim Biophys Acta Rev Cancer 2017; 1868:564-570. [PMID: 29054475 DOI: 10.1016/j.bbcan.2017.10.002] [Citation(s) in RCA: 151] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 10/04/2017] [Accepted: 10/15/2017] [Indexed: 02/06/2023]
Abstract
It is disappointing that only a few patients with hepatocellular carcinoma (HCC) obtain a significant survival benefit from the sorafenib treatment, which is currently regarded as a first-line chemotherapeutic therapy in patients with advanced HCC. Most patients are highly refractory to this therapy. Therefore, it is necessary to identify resistant factors and explore potential protocols that can be used to overcome the resistance or substitute sorafenib once the resistance is formed. In fact, a growing body of studies has been focusing on the resistance mechanisms or the method to overcome it. The limitation of sorafenib efficacy has been partially but not fully elucidated. Moreover, some protocols have shown encouraging outcomes but still need to be further verified in clinical trials. In this review, we summarize the recent findings on the potential mechanisms that contribute to sorafenib resistance and discuss strategies that can be used to improve the treatment outcome.
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Affiliation(s)
- Leilei Niu
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, China
| | - Liping Liu
- Department of Hepatobiliary and Pancreas Surgery, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong Province, China
| | - Shengli Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jianwei Ren
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Paul B S Lai
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China.
| | - George G Chen
- Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, China; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China.
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30
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Wang TH, Wu CH, Yeh CT, Su SC, Hsia SM, Liang KH, Chen CC, Hsueh C, Chen CY. Melatonin suppresses hepatocellular carcinoma progression via lncRNA-CPS1-IT-mediated HIF-1α inactivation. Oncotarget 2017; 8:82280-82293. [PMID: 29137263 PMCID: PMC5669889 DOI: 10.18632/oncotarget.19316] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 06/10/2017] [Indexed: 12/27/2022] Open
Abstract
Melatonin is the primary pineal hormone that relays light/dark cycle information to the circadian system. It was recently reported to exert intrinsic antitumor activity in various cancers. However, the regulatory mechanisms underlying the antitumor activity of melatonin are poorly understood. Moreover, a limited number of studies have addressed the role of melatonin in hepatocellular carcinoma (HCC), a major life-threatening malignancy in both sexes in Taiwan. In this study, we investigated the antitumor effects of melatonin in HCC and explored the regulatory mechanisms underlying these effects. We observed that melatonin significantly inhibited the proliferation, migration, and invasion of HCC cells and significantly induced the expression of the transcription factor FOXA2 in HCC cells. This increase in FOXA2 expression resulted in upregulation of lncRNA-CPS1 intronic transcript 1 (CPS1-IT1), which reduced HIF-1α activity and consequently resulted in the suppression of epithelial-mesenchymal transition (EMT) progression and HCC metastasis. Furthermore, the results of the in vivo experiments confirmed that melatonin exerts tumor suppressive effects by reducing tumor growth. In conclusion, our findings suggested that melatonin inhibited HCC progression by reducing lncRNA-CPS1-IT1-mediated EMT suppression and indicated that melatonin could be a promising treatment for HCC.
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Affiliation(s)
- Tong-Hong Wang
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan.,Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Chi-Hao Wu
- Department of Human Development and Family Studies, National Taiwan Normal University, Taipei, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Shih-Chi Su
- Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Shih-Min Hsia
- School of Nutrition and Health Sciences, College of Nutrition, Taipei Medical University, Taipei, Taiwan
| | - Kung-Hao Liang
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Chin-Chuan Chen
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Graduate Institute of Natural Products, Chang Gung University, Tao-Yuan, Taiwan
| | - Chuen Hsueh
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | - Chi-Yuan Chen
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
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31
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Patitucci C, Couchy G, Bagattin A, Cañeque T, de Reyniès A, Scoazec JY, Rodriguez R, Pontoglio M, Zucman-Rossi J, Pende M, Panasyuk G. Hepatocyte nuclear factor 1α suppresses steatosis-associated liver cancer by inhibiting PPARγ transcription. J Clin Invest 2017; 127:1873-1888. [PMID: 28394260 DOI: 10.1172/jci90327] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 02/16/2017] [Indexed: 12/26/2022] Open
Abstract
Worldwide epidemics of metabolic diseases, including liver steatosis, are associated with an increased frequency of malignancies, showing the highest positive correlation for liver cancer. The heterogeneity of liver cancer represents a clinical challenge. In liver, the transcription factor PPARγ promotes metabolic adaptations of lipogenesis and aerobic glycolysis under the control of Akt2 activity, but the role of PPARγ in liver tumorigenesis is unknown. Here we have combined preclinical mouse models of liver cancer and genetic studies of a human liver biopsy atlas with the aim of identifying putative therapeutic targets in the context of liver steatosis and cancer. We have revealed a protumoral interaction of Akt2 signaling with hepatocyte nuclear factor 1α (HNF1α) and PPARγ, transcription factors that are master regulators of hepatocyte and adipocyte differentiation, respectively. Akt2 phosphorylates and inhibits HNF1α, thus relieving the suppression of hepatic PPARγ expression and promoting tumorigenesis. Finally, we observed that pharmacological inhibition of PPARγ is therapeutically effective in a preclinical murine model of steatosis-associated liver cancer. Taken together, our studies in humans and mice reveal that Akt2 controls hepatic tumorigenesis through crosstalk between HNF1α and PPARγ.
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32
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Zhou M, Zhang XY, Yu X. Overexpression of the long non-coding RNA SPRY4-IT1 promotes tumor cell proliferation and invasion by activating EZH2 in hepatocellular carcinoma. Biomed Pharmacother 2016; 85:348-354. [PMID: 27899259 DOI: 10.1016/j.biopha.2016.11.035] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 11/08/2016] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Increasing evidences have demonstrated that the dysregulation of long non-coding RNAs (lncRNAs) may act as an important role in tumor progression. The long non-coding RNA SPRY4 intronic transcript 1 (SPRY4-IT1) has been reported in some cancer including regulating cell growth, differentiation, apoptosis, and cancer progression. However, the expression and function of SPRY4-IT1 in the progression of hepatocellular carcinoma (HCC) remain largely unknown. METHODS The lncRNA SPRY4-IT1 was detected by quantitative real time PCR (qRT-PCR) in HCC cell lines, CCK8 cell proliferation and transwell invasion assays were performed to detect the GC cell proliferation and invasion abilities. The protein expression of E-cadherin, Vimentin and Twist1 was analyzed by Western blotting assays. Furthermore, RNA immunoprecipitation (RIP) and Chromatin immunoprecipitation (ChIP) assays were used to analyze potential molecular mechanism of SPRY4-IT1 in HCC cells. RESULTS We found that SPRY4-IT1 was up-regulated in HCC cell lines. Further function analysis demonstrated that knockdown of SPRY4-IT1 significantly inhibited HCC cells proliferation and invasion, but over-expression of SPRY4-IT1 had the opposite effects on HCC cells in vitro. Moreover, our results also indicated that SPRY4-IT1 over-expression significantly promoted the epithelial-mesenchymal transition (EMT) by up-regulating the transcription factor Twist1 and EMT marker Vimentin and inhibited the E-cadherin expression in MHCC97L cell. Whereas, knockdown of SPRY4-IT1 suppressed the transcription factor Twist1 and EMT marker Vimentin and increased the E-cadherin expression in MHCC97H cells. Mechanisms investigations showed that SPRY4-IT1 interacted with the EZH2 and epigenetically repressed the E-cadherin expression. In vivo, we also demonstrated that the tumor growth was inhibited in SPRY4-IT1 knockdown group compared with the control group. CONCLUSIONS These results suggested that lncRNA SPRY4-IT1 might be considered as a therapeutic target in HCC.
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Affiliation(s)
- Meng Zhou
- Department of Hepatopancreatobillary Surgery Treatment Center, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei Province, China
| | - Xiao-Yu Zhang
- Division of Gastrointestinal Surgery, Department of General Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, China.
| | - Xi Yu
- Department of Gastroenterology, Long gang District Central Hospital of Shenzhen, No. 6082 Long gang Avenue, Long gang District, Shenzhen, Guangdong, China.
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33
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Goossens N, Hoshida Y. Tratamiento personalizado del carcinoma hepatocelular basado en información molecular: perspectivas futuras. Clin Liver Dis (Hoboken) 2016; 8:S43-S48. [PMID: 31041096 PMCID: PMC6490229 DOI: 10.1002/cld.601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Nicolas Goossens
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer InstituteIcahn School of Medicine at Mount SinaiNew YorkNY, EE. UU,Division of Gastroenterology and HepatologyGeneva University HospitalGinebraSuiza
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer InstituteIcahn School of Medicine at Mount SinaiNew YorkNY, EE. UU
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34
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Berretta M, Rinaldi L, Di Benedetto F, Lleshi A, De Re V, Facchini G, De Paoli P, Di Francia R. Angiogenesis Inhibitors for the Treatment of Hepatocellular Carcinoma. Front Pharmacol 2016; 7:428. [PMID: 27881963 PMCID: PMC5101236 DOI: 10.3389/fphar.2016.00428] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 10/26/2016] [Indexed: 12/12/2022] Open
Abstract
Background: Angiogenesis inhibitors have become an important therapeutic approach in the treatment of hepatocellular carcinoma (HCC) patients. The therapeutic inhibition of angiogenesis of Sorafenib in increasing overall survival of patients with HCC is a fundamental element of the treatment of this disease. Considering the heterogeneous aspects of HCC and to boost therapeutic efficacy, prevail over drug resistance and lessen toxicity, adding antiangiogenic drugs to antiblastic chemotherapy (AC), radiation therapy or other targeted drugs have been evaluated. The matter is additionally complicated by the combination of antiangiogenesis with further AC or biologic drugs. To date, no planned approach to understand which patients are more responsive to a given type of antiangiogenic treatment is available. Conclusion: Large investments in the clinical research are essential to improve treatment response and minimize toxicities for patients with HCC. Future investigations will need to focus on utilizing patterns of genetic information to classify HCC into groups that display similar prognosis and treatment sensitivity, and combining targeted therapies with AC producing enhanced anti-tumor effect. In this review the current panel of available antiangiogenic therapies for the treatment of HCC have been analyzed. In addition current clinical trials are also reported herein.
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Affiliation(s)
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Metabolic and Geriatric Sciences, Second University of Naples Naples, Italy
| | - Fabrizio Di Benedetto
- Liver and Multivisceral Transplant Center, University of Modena and Reggio Emilia Modena, Italy
| | - Arben Lleshi
- Department of Medical Oncology, National Cancer Institute Aviano, Italy
| | - Vallì De Re
- Bioimmunotherapy of Human Cancers Unit, Centro di Riferimento Oncologico (CRO) National Cancer Institute Aviano, Italy
| | - Gaetano Facchini
- Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS Naples Naples, Italy
| | - Paolo De Paoli
- Scientific Directorate, Centro di Riferimento Oncologico (CRO) National Cancer Institute Aviano, Italy
| | - Raffaele Di Francia
- Department of Hematology, Istituto Nazionale Tumori "Fondazione G. Pascale"-IRCCS Naples Naples, Italy
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35
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Trojan J, Waidmann O. Role of regorafenib as second-line therapy and landscape of investigational treatment options in advanced hepatocellular carcinoma. J Hepatocell Carcinoma 2016; 3:31-36. [PMID: 27703962 PMCID: PMC5036543 DOI: 10.2147/jhc.s112537] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Sorafenib is still the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). In recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development due to either toxicity or lack of benefit. Recently, data of the RESORCE trial, a placebo-controlled Phase III study that evaluated the efficacy and safety of regorafenib in patients with HCC and documented disease progression after systemic first-line treatment with sorafenib, were presented at the ESMO World Congress on Gastrointestinal Cancer, 2016. Regorafenib treatment resulted in a 2.8-month survival benefit compared to placebo (10.6 months vs 7.8 months). Side effects were consistent with the known profile of regorafenib. The approval of regorafenib for this indication is expected in 2017. Further candidate agents in Phase III evaluation for second-line treatment of patients with HCC are the MET inhibitors tivantinib and cabozantinib, the vascular endothelial growth factor receptor-2 antibody ramucirumab, and the programmed death receptor-1 (PD-1) blocking antibody pembrolizumab. Furthermore, results from two first-line trials with either the tyrosine kinase inhibitor lenvatinib or the PD-1 antibody nivolumabin in comparison to sorafenib are awaited in the near future and might further change the treatment sequence of advanced HCC.
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Affiliation(s)
- Jörg Trojan
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Germany
| | - Oliver Waidmann
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Germany
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36
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Wang TH, Lin YS, Chen Y, Yeh CT, Huang YL, Hsieh TH, Shieh TM, Hsueh C, Chen TC. Long non-coding RNA AOC4P suppresses hepatocellular carcinoma metastasis by enhancing vimentin degradation and inhibiting epithelial-mesenchymal transition. Oncotarget 2016; 6:23342-57. [PMID: 26160837 PMCID: PMC4695122 DOI: 10.18632/oncotarget.4344] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 06/12/2015] [Indexed: 12/31/2022] Open
Abstract
Increasing evidence indicates that long non-coding RNAs (lncRNAs) regulate diverse cellular processes, including cell growth, differentiation, apoptosis, and cancer progression. However, the function of lncRNAs in the progression of hepatocellular carcinoma (HCC) remains largely unknown. We performed a comprehensive microarray analysis of lncRNA expression in human HCC samples. After validation in 108 HCC specimens, we identified a differentially expressed novel tumor suppressive lncRNA termed amine oxidase, copper containing 4, pseudogene (AOC4P). The level of AOC4P expression was significantly downregulated in 68% of HCC samples and negatively correlated with advanced clinical stage, capsule invasion and vessel invasion. Low AOC4P expression correlated with poor prognostic outcomes, serving as an independent prognostic factor for HCC. In vitro functional assays indicated that AOC4P overexpression significantly reduced cell proliferation, migration and invasion by inhibiting the epithelial-mesenchymal transition (EMT). RNA immunoprecipitation assays demonstrated that AOC4P binds to vimentin and promotes its degradation. Animal model experiments confirmed the ability of AOC4P to suppress tumor growth and metastasis. Taken together, our findings suggest that AOC4P lncRNA acts as an HCC tumor suppressor by enhancing vimentin degradation and suppressing the EMT. By clarifying the mechanisms underlying HCC progression, these findings promote the development of novel therapeutic strategies for HCC.
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Affiliation(s)
- Tong-Hong Wang
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Yong-Shiang Lin
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | - Ying Chen
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Chau-Ting Yeh
- Department of Hepato-Gastroenterology, Liver Research Center, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
| | - Yen-Lin Huang
- Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | | | - Tzong-Ming Shieh
- Department of Dental Hygiene, College of Health Care, China Medical University, Taichung, Taiwan
| | - Chuen Hsueh
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
| | - Tse-Ching Chen
- Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.,Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chang Gung University School of Medicine, Tao-Yuan, Taiwan
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37
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Dumortier J, Dharancy S, Calmus Y, Duvoux C, Durand F, Salamé E, Saliba F. Use of everolimus in liver transplantation: The French experience. Transplant Rev (Orlando) 2016; 30:161-70. [DOI: 10.1016/j.trre.2015.12.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Accepted: 12/14/2015] [Indexed: 12/18/2022]
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38
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Thillai K, Ross P, Sarker D. Molecularly targeted therapy for advanced hepatocellular carcinoma - a drug development crisis? World J Gastrointest Oncol 2016; 8:173-85. [PMID: 26909132 PMCID: PMC4753168 DOI: 10.4251/wjgo.v8.i2.173] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Revised: 11/16/2015] [Accepted: 12/09/2015] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma is the fastest growing cause of cancer related death globally. Sorafenib, a multi-targeted kinase inhibitor, is the only drug proven to improve outcomes in patients with advanced disease offering modest survival benefit. Although comprehensive genomic mapping has improved understanding of the genetic aberrations in hepatocellular cancer (HCC), this knowledge has not yet impacted clinical care. The last few years have seen the failure of several first and second line phase III clinical trials of novel molecularly targeted therapies, warranting a change in the way new therapies are investigated in HCC. Potential reasons for these failures include clinical and molecular heterogeneity, trial design and a lack of biomarkers. This review discusses the current crisis in HCC drug development and how we should learn from recent trial failures to develop a more effective personalised treatment paradigm for patients with HCC.
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39
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Guo YL, Kong QS, Liu HS, Tan WB. Drug resistance effects of ribosomal protein L24 overexpression in hepatocellular carcinoma HepG2 cells. Asian Pac J Cancer Prev 2015; 15:9853-7. [PMID: 25520117 DOI: 10.7314/apjcp.2014.15.22.9853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The morbidity and mortality rate of liver cancer continues to rise in China and advanced cases respond poorly to chemotherapy. Ribosomal protein L24 has been reported to be a potential therapeutic target whose depletion or acetylation inhibits polysome assembly and cell growth of cancer. MATERIALS AND METHODS Total RNA of cultured amycin-resistant and susceptible HepG2 cells was isolated, and real time quantitative RT-PCR were used to indicate differences between amycin-resistant and susceptible strains of HepG2 cells. Viability assays were used to determine amycin resistance in RPL24 transfected and control vector and null- transfected HepG2 cell lines. RESULTS The ribosomal protein L24 transcription level was 7.7 times higher in the drug-resistant HepG2 cells as compared to susceptible cells on quantitative RT-PCR analysis. This was associated with enhanced drug resistance as determined by methyl tritiated thymidine (3H-TdR) incorporation. CONCLUSIONS The ribosomal protein L24 gene may have effects on drug resistance mechanisms in hepatocellular carcinoma HepG2 cells.
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Affiliation(s)
- Yong-Li Guo
- Oncology Department of the Jining First People's Hospital, Jining, Shandong, People's Republic of China E-mail :
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40
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Schulze K, Zucman-Rossi J. Current issues on genomic heterogeneity in hepatocellular carcinoma and its implication in clinical practice. Hepat Oncol 2015; 2:291-302. [PMID: 30191009 DOI: 10.2217/hep.15.16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease leading to a major diversity. Since staging systems are used in patient care, molecular and histopathological features remain to be incorporated in management algorithms. HCC, as other malignant solid tumors, exhibit a complex genetic diversity and genomic instability, driving tumorigenesis. The recent development of deep sequencing techniques has revealed different subgroups of tumors defined by specific patterns of genomic alterations that are related to clinical and histopathological diversity in HCC. Additionally, several genomic defects identified in HCC will be used in the future to develop clinical trial design for tumorized treatment.
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Affiliation(s)
- Kornelius Schulze
- Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hématologie, F-75010 Paris, France.,Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, F-75013 Paris, France.,Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, F-93000 Bobigny, France.,Université Paris Diderot, F-75013 Paris, France.,Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hématologie, F-75010 Paris, France.,Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, F-75013 Paris, France.,Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, F-93000 Bobigny, France.,Université Paris Diderot, F-75013 Paris, France
| | - Jessica Zucman-Rossi
- Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hématologie, F-75010 Paris, France.,Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, F-75013 Paris, France.,Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, F-93000 Bobigny, France.,Université Paris Diderot, F-75013 Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France.,Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hématologie, F-75010 Paris, France.,Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, F-75013 Paris, France.,Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Médecine, Biologie Humaine, F-93000 Bobigny, France.,Université Paris Diderot, F-75013 Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, F-75015 Paris, France
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Facciorusso A, Licinio R, Carr BI, Di Leo A, Barone M. MEK 1/2 inhibitors in the treatment of hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2015; 9:993-1003. [PMID: 25915713 DOI: 10.1586/17474124.2015.1040763] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Sorafenib is the only approved systemic treatment for advanced hepatocellular carcinoma patients and all the recently published randomized controlled trials on new systemic drugs have been unsuccessful. This is likely due to a lack of understanding of tumor progression, molecular drivers, and liver toxicity, as well as flaws in trial design. An important signaling pathway in hepatocarcinogenesis is the MEK cascade involved in various cellular responses, including adaptation and survival. A key role in this cascade is played by MEK, of which MEK 1/2 represent the prototypes and an interesting target for new oncological drugs. This review analyzes recent developments and future perspectives on the role of MEK inhibitors in hepatocellular carcinoma treatment.
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Affiliation(s)
- Antonio Facciorusso
- Gastroenterology Unit, Department of Medical and Surgical Sciences, University of Foggia, Ospedali Riuniti Foggia, Italy
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42
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Waidmann O, Trojan J. Novel drugs in clinical development for hepatocellular carcinoma. Expert Opin Investig Drugs 2015; 24:1075-82. [PMID: 26108356 DOI: 10.1517/13543784.2015.1058776] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma (HCC). Within recent years, several investigational agents mainly targeting angiogenesis failed in late-phase clinical development either due to toxicity or lack of benefit. AREAS COVERED This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC. EXPERT OPINION In unselected patients with advanced HCC, disappointing results have been reported from several large trials. However, in two subgroups encouraging results have been achieved. Treatment with the MET inhibitor tivantinib resulted in a substantial survival benefit in the subgroup of MET overexpressing tumors in a randomized Phase II trial. Furthermore, the vascular endothelial growth factor receptor 2 antibody ramucirumab resulted in improved overall survival in patients with baseline α-fetoprotein (AFP) ≥ 400 ng/ml in a Phase III trial. These two agents, and several others, will be further developed in HCC. Moreover, immunotherapeutics such as checkpoint inhibitors, programmed death receptor-1 blocking antibodies and oncolytic viruses are under investigation in advanced HCC.
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Affiliation(s)
- Oliver Waidmann
- Universitätsklinikum Frankfurt, Medizinische Klinik 1 , Theodor-Stern-Kai 7, Frankfurt am Main , Germany +49 0 69 6301 7860 ; +49 0 69 6301 6448 ;
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Goossens N, Hoshida Y. Personalized management of hepatocellular carcinoma based on molecular information: future prospects. Clin Liver Dis (Hoboken) 2015; 5. [PMID: 26213619 PMCID: PMC4512174 DOI: 10.1002/cld.483] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Affiliation(s)
- Nicolas Goossens
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer InstituteIcahn School of Medicine at Mount SinaiNew YorkNY,Division of Gastroenterology and HepatologyGeneva University HospitalGenevaSwitzerland
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer InstituteIcahn School of Medicine at Mount SinaiNew YorkNY
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Jin H, Zhang Y, You H, Tao X, Wang C, Jin G, Wang N, Ruan H, Gu D, Huo X, Cong W, Qin W. Prognostic significance of kynurenine 3-monooxygenase and effects on proliferation, migration, and invasion of human hepatocellular carcinoma. Sci Rep 2015; 5:10466. [PMID: 26099564 PMCID: PMC4479133 DOI: 10.1038/srep10466] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 04/15/2015] [Indexed: 12/13/2022] Open
Abstract
Kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the kynurenine pathway of tryptophan degradation and plays a critical role in Huntington's and Alzheimer's diseases. This study aimed to examine the expression of KMO in human hepatocellular carcinoma (HCC) and investigate the relationship between its expression and prognosis of HCC patients. We first analyzed KMO expression in 120 paired HCC samples (HCC tissues vs matched adjacent non-cancerous liver tissues), and 205 clinical HCC specimens using immunohistochemistry (IHC). Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. The results of IHC analysis showed that KMO expression was significantly higher in HCC tissues than that in normal liver tissues (all p < 0.05). Survival and recurrence analyses showed that KMO was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR) (both p<0.01). And in vitro studies revealed that KMO positively regulated proliferation, migration, and invasion of HCC cells. These results suggest that KMO exhibits tumor-promoting effects towards HCC and it may serve as a novel prognostic marker in HCC.
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Affiliation(s)
- Haojie Jin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Yurong Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Haiyan You
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Xuemei Tao
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Cun Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Guangzhi Jin
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University
| | - Ning Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Haoyu Ruan
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Dishui Gu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Xisong Huo
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
| | - Wenming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University
| | - Wenxin Qin
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine
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